HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 45-50 million people infected worldwide at the end of 2011. The number of cases of HIV and AIDS (acquired immunodeficiency syndrome) has risen rapidly. In 2005, approximately 5.0 million new infections were reported, and 3.1 million people died from AIDS. Currently available drugs for the treatment of HIV include nucleoside reverse transcriptase (RT) inhibitors: zidovudine (or AZT or RETROVIR®), didanosine (or VIDEX®), stavudine (or ZERIT®), lamivudine (or 3TC or EPIVIR®), zalcitabine (or DDC or HIVID®), abacavir succinate (or ZIAGEN®), Tenofovir disoproxil fumarate salt (or VIREAD®), emtricitabine (or FTC-EMTRIVA®), COMBIVIR® (contains -3TC plus AZT), TRIZIVIR® (contains abacavir, lamivudine, and zidovudine), Epzicom (contains abacavir and lamivudine), TRUVADA® (contains VIREAD® and EMTRIVA®); non-nucleoside reverse transcriptase inhibitors: rilpivirine (or Edurant), nevirapine (or VIRAMUNE®), delavirdine (or RESCRIPTOR®) and efavirenz (or SUSTIVA®), Atripla (TRUVADA®+SUSTIVA®), Complera (TRUVADA®+Edurant), and etravirine, and peptidomimetic protease inhibitors or approved formulations: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, KALETRA® (lopinavir and Ritonavir), darunavir, atazanavir (REYATAZ®) and tipranavir (APTIVUS®), and integrase inhibitors such as raltegravir (Isentress), and entry inhibitors such as enfuvirtide (T-20) (FUZEON®) and maraviroc (Selzentry). Other drugs are slated for approval within the next few years, or are earlier on in various stages of development.
In addition to the foregoing, HIV attachment inhibitors are a novel subclass of antiviral compounds that bind to the HIV surface glycoprotein gp120, and interfere with the interaction between the surface protein gp120 and the host cell receptor CD4. Thus, they prevent HIV from attaching to the human CD4 T-cell, and block HIV replication in the first stage of the HIV life cycle. The properties of HIV attachment inhibitors have been improved in an effort to obtain compounds with maximized utility and efficacy as antiviral agents.
One HIV attachment inhibitor compound, in particular, has now shown considerable prowess against HIV. This compound is known as 1-(4-benzoyl-piperazin-1-yl)-2-[4-methoxy-7-(3-methyl-[1,2,4]triazol-1-yl)-1H-pyrralo[2,3-c]pyridine-3-yl]-ethane-1,2-dione, which is set forth and described in U.S. Pat. No. 7,354,924, which is incorporated herein in its entirety:

Further, a phosphate ester prodrug of the above parent compound has now been developed. This compound is 1-benzoyl-4-[2-[4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1-[phosphonooxy)methyl]-1H-pyrrolo[2,3-c]pyridin-3-yl]-1,2-dioxoethyl]-piperazine. It is set forth and described in U.S. Pat. No. 7,745,625, which is incorporated by reference herein it its entirety. The compound is represented by the formula below:

A formulation with the above phosphate ester prodrug in tris salt form, together with hydroxypropyl methyl cellulose (HPMC), has been set forth and described in U.S. Publication No. 2010/0056540 A1, also incorporated by reference herein.
In certain other instances, however, there have been issues with formulating the API prodrug with excipients. The crystalline form of the input, unprocessed prodrug is typically characterized by highly chargeable, fragile needles with high aspect ratio, low bulk density and very poor flow capability, whether as API alone or when further mixed with excipients. Comparative FIG. 1 is a photograph of the unprocessed, crystalline phosphate ester prodrug compound. These characteristics can present significant challenges with either dry or wet granulation techniques. For dry granulation, poor powder flow presents a major challenge in controlling the hopper flow and feed into the roller compactor. With wet granulation, it has been difficult to control the change in form associated with the overall process, thereby often resulting in poor stability of the final product formulation.
What is now needed in the art is a new processing method for formulating the HIV attachment inhibitor phosphate ester prodrug compound with excipients, including HPMC. This method should produce a formulation with high API content with good release characteristics, as well as good flow, improved bulk density, and high compactability.